Microsatellite Instability Pathway and EMAST in Colorectal Cancer

Abstract

Microsatellite instability (MSI) refers to the biochemical detection of frameshifted microsatellite sequences from genomic DNA. Genesis of MSI is due to defective DNA mismatch repair (MMR) that fails to correct post DNA replicative slippage mistakes at microsatellites. Most of the estimated 100,000 genomic microsatellites are non-coding; however, ~150-300 microsatellites are coding such that, when frameshifted during the pathogenesis of an MSI tumor, can generate immunogenic neopeptide antigens that limit the growth of tumor and prolong patient survival. In addition to the immune reaction and longer survival, patients with MSI colorectal cancers tend to have poorly differentiated tumors with mucinous features that are located in the right colon. Patients with MSI tumors are more resistant to 5-fluorouracil-based adjuvant chemotherapy but may be responsive to PD-1 immune checkpoint blockade. Specific defects of MMR function not only drive MSI but also elevate microsatellite alterations at selected tetranucleotide repeats that may further modify patient outcome.

Keywords: Constitutional Mismatch Repair Deficiency syndrome; DNA microsatellites; DNA mismatch repair; DNA repair; EMAST (elevated microsatellelite alterations at selected tetranucleotide repeats); Lynch syndrome; Lynch-like syndrome; MLH1 hypermethylation; MSH3; colorectal cancer; dinucleotide repeats; familial; microsatellite instability; mononucleotide repeats; patient outcome; patient survival; sporadic; tetranucleotide repeats; trinucleotide repeats.

Figure 1

Spectrum of MMR gene and protein defects and category of frameshift microsatellite mutation to define MSI-H, MSI-L, and EMAST.

Figure 2

Genetic path of colonic neoplasia with loss of MMR function.

Figure 3

Schema showing effect of inflammation on MMR-defective and MMR-intact cancers.